This invention relates to novel, antilipolytically active thiophene derivatives and to process for the preparation and use thereof.
Pathologically high blood serum concentrations of triglycerides are held responsible, inter alia, for the origination and progression of arteriosclerotic changes of the blood vessel wall. The triglycerides in the serum originate not only from food intake but also from the liver, where they are synthesized from the blood, in part with the use of free fatty acids (FFA). A lowering of the FFA content in the serum results in a lowering of the triglyceride condentration in the liver and in the blood. BIZZI, VENERONI, and GARATTINI, J. Pharm. Pharmac. 18, 611, 1966; PAOLETTI and PUGLISI, Naunyl-Schmeidebergs Arch. Pharmak., 269, 317, 1971.
Since the FFA concentration in the serum depends primarily on the extent to which the triglyceride is split in the fatty tissue (lipolysis), a pharmacological inhibition of this process represents an effective measure for lowering the triglyceride level in the serum and to prevent arteriosclerotic changes of blood vessels. This was proven by animal experiments. BIZZI, VENERONI, and GARATTINI, J. Pharm. Pharmac. 18, 611, 1966; BIZZI, GARATTINI, VENERONI, HOWARD, GRESHAM, and JENNINGS, Atherosclerosis, in print, 1974. Also in humans, a reduction of the triglyceride concentration in the serum was measured after treatment with agents which inhibit lipolysis. BERINGER, BAENDER, GLANINGER, MAYRHOFER, and SCHNAK, Horm. Metab. Res. 2, 81, 1970.
Moreover, a reduction in the FFA concentration in the serum by lipolysis inhibition in the fatty tissue is also a sensible therapeutic principle for the treatment of diabetes mellitus. In accordance with investigations conducted by RANDLE and collaborators (RANDLE, P. J. in B. S. LEIBEL and G. A. WRENSHALL, Editors: On the Nature and Treatment of Diabetes, Excerpta Medica Foundation, Amsterdam-New York-London-Milan-Tokyo-Buenos Aires, p. 361, 1965), FFA's interfere with the utilization of glucose for the purpose of obtaining energy in the periphery of the body (musculature). Glucose absorption into the muscle cells is a process dependent on insulin. Since insulin simultaneously inhibits lipolysis and thus the transfer of FFA from the fatty tissue of the blood, the glucose utilization in the body periphery is disturbed for a dual reason in diabetes mellitus, which is characterized by restricted insulin secretion and production.
Primarily, the lack of insulin leads to a disturbance in the glucose absorption by the muscle cells. This disturbance is aggravated by the simultaneously increase in the FFA concentration in the blood and the concomitant, increased FFA fed to the body periphery. This factor is eliminated when lipolysis in the fatty tissue is pharmacologically inhibited; glucose utilization is improved and elevated blood glucose concentration is lowered. This has been shown in experiments on rats with insulin deficiency. FROESCH, WALDVOGEL, MEYER, JAKOB, and LABHART, Mol. Pharmacology, 3, 442, 1967. It can be confirmed in diabetics by improved glucose tolerance, a lowering of elevated blood glucose levels and a reduction of glucose in the urine. In this connection, agents inhibiting lipolysis either proved to be effective in monotherapy or were capable of again normalizing the defective carbohydrate metabolism in secondary failures of therapy with .beta.-cytotropic sulfonyl ureas and/or sulfonyl ureas and biguanides, in combination with these medicines. BERINGER, BAENDER, GLANINGER, MAYRHOFER, and SCHNACK, Horm. Metab. Res., 2, 81, 1970; GEYER and SOKOPP, Vienna, "Klin. Wschr." 81, 701, 1969; GEYER and SOKOPP, "Med. u. Ernaehr." 10, 115, 1969; NEUMANN, MICHAELIS, BIBERGEIL, and WULFERT, "Dtsch. Ges. Wesen" 27, 972, 1972.
Compounds heretofore used in such investigations as agents for inhibiting lipolysis, such as nicotinic acid, 3-pyridinemethanol, 5-(3-pyridyl)-tetrazole, 3,5-dimethylpyrazole, 3,5-dimethylisoxazole; the active metabolites 5-methylpyrazole-3-carboxylic acid and 5-methylisoxazole-3-carboxylic acid, formed in the organism from the two last-mentioned compounds; various other pyrazole and isoxazole derivatives; as well as a number of adenosine derivatives, effect an initial lowering of serum FFA. However, they cannot be employed for a long-term therapy of metabolic anomalies, for various reasons. Except for the adenosine derivatives, all above-mentioned compounds, especially nicotinic acid and compounds derived therefrom, after diminution of their FFA-lowering activity, result in an increase of free fatty acids in the serum, overshooting the initial level (rebound phenomenon), thus nullifying the positive consequences of their initial effect. BIZZI and GARATTINI in: Metabolic Effects of Nicotinic Acid and Its Derivatives, Hans-Huber publishers, Berne, p. 207, 1971. Moreover, pyrazole and isoxazole derivatives, as well as pyridyltetrazole, lose their lipolysis-inhibiting capacity upon repeated application on successive days, after a shorter or longer period of time, and thus lose their ability to lower the concentration of FFA in the serum. This behavior, called tachyphylaxis, was observed in animal experiments. BIZZI and GARATTINI in: Metabolic Effects of Nicotinic Acid and Its Derivatives, Hans-Huber publishers, Berne, 1971, p. 207; FROESCH, WALDVOGEL, MEYER, JAKOB, and LABHART, Mol. Pharmacol. 3, 442, 1967; SCHILLINGER and LOGE, Biochem. Pharmacol., in print, 1974. It was confirmed in man made during the clinical application of 5-methylpyrazole-3-carboxylic acid and 5-methylisozazole-3acid. NEUMANN, MICHAELIS, BIBERGEIL, and WULFERT, "Dtsch. Ges. Wesen" 27 972, 1972; GEYER and SOKOPP, Acta endocr. (Kbh.) Suppl. 173, 127, 1973. In accordance with the above-mentioned findings, the phenomenon of tachyphylaxis need not necessarily be related to the rebound phenomenon but, just as the latter, the former phenomenon is prohibitive for long term therapy.
Antilipolytically effective adenosine derivatives exhibit neither a rise in serum FFA, overshooting the starting level, after the initial reduction, nor a loss in effectiveness upon repeated administration. SCHILLINGER and LODGE, Biochem. Pharmacol., in print, 1974. However, these compounds possess only an extremely small therapeutic range, since they affect cardiac activity at lipolytically effective or only slightly higher doses, and lead to a drop in the heartbeat frequency. MANNESMANN, publication in preparation, 1974. Due to this dangerous effect on the cardiovascular system, adenosine derivatives cannot be used in long-term therapy in humans.
In the search for lipolysis-inhibiting agents suitable for a long-term administration to humans, it has been found, surprisingly, that the novel thiophene derivatives of this invention exhibit neither the phenomenon of tachyphylaxis nor that of overshooting the free fatty acid level after an initial reduction (rebound phenomenon). Moreover, no effect on heartbeat frequency was seen and the therapeutic dosage range is very wide.